| 1. Round | 13/08/2021 | Gudja United | - | Sirens FC | 0:1 | ||||
| 2. Round | 20/08/2021 | Sirens FC | - | Mosta FC | 1:1 | ||||
| 4. Round | 18/09/2021 | St. Luċija FC | - | Sirens FC | 1:3 |  |
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| 5. Round | 26/09/2021 | Sirens FC | - | Sliema Wanderers | 2:2 | |
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| 6. Round | 17/10/2021 | Valletta FC | - | Sirens FC | 3:1 | |
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| 7. Round | 24/10/2021 | Sirens FC | - | Birkirkara FC | 3:2 | ||||
| 8. Round | 30/10/2021 | Hamrun Spartans | - | Sirens FC | 1:0 | |
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| 10. Round | 27/11/2021 | Floriana FC | - | Sirens FC | 1:2 | ||||
| 11. Round | 04/12/2021 | Sirens FC | - | Gżira United | 1:3 | |
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| 14. Round | 18/01/2022 | Hibernians FC | - | Sirens FC | 1:1 | ||||
| 15. Round | 23/01/2022 | Sirens FC | - | St. Luċija FC | 2:1 | |
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| 16. Round | 29/01/2022 | Sliema Wanderers | - | Sirens FC | 1:0 | ||||
| 17. Round | 06/02/2022 | Sirens FC | - | Valletta FC | 2:1 | |
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| 18. Round | 13/02/2022 | Birkirkara FC | - | Sirens FC | 1:1 | |
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| 20. Round | 27/02/2022 | Balzan FC | - | Sirens FC | 2:1 | |
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| 21. Round | 06/03/2022 | Sirens FC | - | Floriana FC | 0:3 | ||||
| 22. Round | 12/03/2022 | Gżira United | - | Sirens FC | 2:1 |
Italy